Attenuation of cue-controlled cocaine-seeking by a selective D3 dopamine receptor antagonist SB-277011-A.

Conditioned stimuli (CS) previously paired with drugs of abuse can elicit cravings in humans, relapse to drug use, and can also reinforce drug-seeking behavior in both humans and animals, events that are believed to be subserved in part by activation of the mesolimbic dopamine system. Converging anatomical, pharmacological, and behavioral evidence implicates dopamine D(3) receptors in the mechanisms underlying cue-controlled behaviors. The purpose of the present study was therefore to investigate the effects on cocaine-seeking behavior of a novel D(3) receptor antagonist, SB-277011-A, which is 100-fold more selective for D(3) over D(2) dopamine receptors. We have established previously that second-order schedules of reinforcement provide an animal model of cue-controlled drug-seeking both prior to and after cocaine has been self-administered. SB-277011-A dose-dependently decreased cocaine-seeking maintained by a cocaine-associated conditioned reinforcer in both the first, drug-free interval and also following self-administration of cocaine. At higher doses, SB-277011-A also increased the latency to receive the first CS presentation and cocaine infusion, thereby decreasing the number of cocaine infusions self-administered under the second-order schedule of reinforcement. SB-277011-A had no effect on cocaine intake under an FR-1 schedule of reinforcement, or on responding for sucrose under a second-order schedule of reinforcement, at any dose tested. These results therefore suggest that D(3) dopamine receptors may be critically involved in cue-controlled drug-seeking behavior independently of any interaction with the reinforcing effects of cocaine itself, and may therefore provide a therapeutic target in the treatment of relapse to cocaine use induced by CSs.     

Dopamine D3 receptor modulation of dopamine efflux in the rat nucleus accumbens

The effect of antipsychotics on electrically evoked dopamine efflux in the rat nucleus accumbens core and shell was investigated, using in vitro fast cyclic voltammetry. In the nucleus accumbens core, the dopamine D2/D3 receptor agonist, (+/-)7-OH-DPAT ((+/-)-2-dipropylamino-7-hydroxy-1,2,3,4-tetrahydronaphthalene), inhibited dopamine efflux with a pEC50 of 8.1. Clozapine, haloperidol, sulpiride and the selective dopamine D3 receptor antagonist, SB-277011-A, had no effect on dopamine efflux per se but all attenuated the (+/-)7-OH-DPAT-induced-inhibition of dopamine efflux, with pA2 values of 6.6, 7.9, 7.0 and 7.6, respectively. In the nucleus accumbens shell, (+/-)7-OH-DPAT inhibited dopamine efflux with a pEC50 of 8.3. Clozapine and SB-277011-A had no effect on dopamine efflux. In contrast, haloperidol and sulpiride significantly increased dopamine efflux through a D2 receptor-mediated mechanism. Clozapine, haloperidol, sulpiride and SB-277011-A attenuated the (+/-)7-OH-DPAT-induced inhibition with pA2 values of 7.3, 8.6, 7.6 and 8.2, respectively. These data demonstrate that dopamine efflux is modulated by both dopamine D2 and D3 receptors in the rat nucleus accumbens.     

Selective antagonism at dopamine D3 receptors attenuates cocaine-seeking behaviour in the rat

Dopamine (DA) D3 receptors have been suggested to play a role in mechanisms underlying the ability of drug-associated cues to induce drug-seeking behaviour. The present study investigated whether SB-277011-A, a selective DA D3 receptor antagonist, modulates reinstatement of cocaine-seeking behaviour induced by cocaine-associated stimuli. The study also explored whether or not this modulation is generable to seeking behaviours associated with a nutritive reinforcer such as sucrose. Separate groups of rats were trained to associate discriminative stimuli (SD) with the availability of cocaine or sucrose pellets vs. non-reward under a FR1 schedule of reinforcement. Each reinforced response was followed by a response-cue signalling a 20-s time-out (TO). After the self-administration training criterion was met, rats underwent extinction during which cocaine, sucrose pellets and SDs were withheld. Reinstatement tests, separated by 3 d during which rates of responding under extinction conditions remained at the criterion, were performed by presenting SDs non-contingently together with the contingent presentation of response-cues signalling a 20-s TO. Within- and between-subjects experimental designs revealed that 10 and 30 mg/kg SB-277011-A attenuated reinstatement of cocaine-seeking. SB-277011-A (10 mg/kg) did not modify conditioned reinstatement triggered by sucrose pellet-associated cues. These results, provided they can be extrapolated to abstinent human addicts, suggest the potential therapeutic use of selective DA D3 receptor antagonists for the prevention of cue-controlled cocaine-seeking and relapse.     

Role of dopamine D3 receptors in the expression of conditioned fear in rats

There has been considerable interest in the role of dopamine D(3) receptors in appetitive conditioning but few studies have examined their role in aversive conditioning. The present study examined the effect of the dopamine D(3) receptor-preferring partial agonist BP 897 (1-(4-(2-naphthoyl-amino)butyl)-4-(2-methoxyhenyl)-1A-piperazine hydrochloride) and the selective dopamine D(3) receptor antagonist SB-277011A (trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]syclohexyl]4-quinolininecarboxamide]) on the expression and acquisition of fear conditioning. Rats (N=143) received 3 conditioned stimulus-shock pairings and then received 15 conditioned stimulus-alone presentations (3 per day) while lever pressing for food. Response suppression was taken as the behavioral measure of fear. Rats showed strong suppression to the conditioned stimulus after it had been paired with shock and suppression progressively weakened over conditioned stimulus-alone presentations. In experiment 1, rats that received BP 897 (1.0, 2.0 mg/kg i.p.) or SB-277011A (10.0 mg/kg i.p.) prior to conditioned stimulus-alone presentation sessions showed reduced suppression to the conditioned stimulus as compared to rats that received vehicle or lower doses of drug (0, 0.1 mg/kg BP 897; 0, 0.5, 5.0 mg/kg SB-277011A). Injections of BP 897 (1.0, 2.0 mg/kg) or SB-277011A (10.0 mg/kg) prior to conditioned stimulus-shock pairings did not significantly affect subsequent response suppression. Thus, BP 897 and SB-277011A dose-dependently attenuated the expression but not the acquisition of conditioned fear. These findings suggest that BP 897 and SB-277011A reduce the control of responding by aversively conditioned stimuli.     

Selective antagonist at D3 receptors, but not non-selective partial agonists, influences the expression of cocaine-induced conditioned place preference in free-feeding rats

The non-selective dopamine (DA) D(3) partial agonist BP 897 influenced rats' seeking behavior induced by cocaine-associated cues but there are contradictions about its ability to modulate cocaine-induced conditioned place preference (CPP), and mechanisms involved. We therefore re-evaluated its activity on both acquisition and expression of these behaviors, taking into consideration the actual brain concentrations of unchanged drug and its potential active metabolite 1-(2-methoxyphenyl)-piperazine (oOCH(3)PP), as well as its negative motivational properties. BP 897 induced conditioned place aversion (CPA) at 3 mg/kg, but not at 0.3 and 1 mg/kg. However, in this range of amply spaced doses BP 897 did not affect the acquisition and expression of cocaine (10 mg/kg i.p.) CPP in rats, although its brain concentrations were well above those affecting in vitro D(3) receptors. Concentrations of oOCH(3)PP were below the limits of quantification of the analytical procedure. As concerns the expression behavior, its structurally and pharmacologically related derivative N-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl]benzo[b]furan-2-carboxamide (1 and 3 mg/kg, i.p.) also had no such effect. By contrast, the selective D(3) receptor antagonist SB-277011-A (3 mg/kg, i.p.) antagonized the expression of cocaine-induced CPP, supporting the suggestion that "full" antagonist activity at D(3) receptors is necessary to prevent 10 mg/kg cocaine-induced place conditioning in free-feeding rats.     

Selective antagonism at dopamine D3 receptors prevents nicotine-triggered relapse to nicotine-seeking behavior.

Drugs of abuse, including, nicotine have been shown to enhance brain reward functions in the mesocortico-limbic dopamine (DA) system in general, and the nucleus accumbens in particular. The latter occupies a prominent position in the ventral striatum and expresses a high density of DA D(3) receptors. As such, the present study aimed at investigating the effect of the selective D(3) receptor antagonist SB-277011-A on both the stable maintenance of intravenous nicotine self-administration and nicotine-triggered relapse to nicotine-seeking behavior in the rat. SB-277011-A (3-10 mg/kg i.p.) significantly reduced reinstatement of nicotine-seeking behavior without affecting nicotine self-administration per se. These results suggest that DA D(3) receptors are involved in the reinstatement of nicotine-seeking behavior independently of any interaction with the primary reinforcing effects of nicotine itself. These findings point toward the potential use of selective DA D(3) receptor antagonists for the pharmacotherapeutic management of relapse to drug-seeking behaviors.     

The selective dopamine D3 receptor antagonist SB-277011-A attenuates ethanol consumption in ethanol preferring (P) and non-preferring (NP) rats

The mesolimbic dopamine (DA) system plays an important role in mediating addiction to alcohol and other drugs of abuse. Recent evidence points toward the role of the DA D3 receptor (D3R) in drug-induced reward, drug-taking, as well as cue-, drug-, and stress-triggered relapse to drug-seeking behavior. Accordingly, the present study examined the effects of acute selective antagonism of the D3R on ethanol consumption in alcohol Preferring (P) and Non-Preferring (NP) rats. We employed the two-bottle choice paradigm to monitor ethanol consumption in these rats before and after treatment with 3, 10, and 30 mg/kg (i.p.) of the selective D3R antagonist SB-277011-A. Results indicated a significant attenuation in ethanol preference, intake and lick responses in P rats treated with 10 and 30 mg/kg SB-277011-A. A similar, though not as robust effect was observed in ethanol consumption in the NP rats when treated with 30 mg/kg SB-277011-A. Finally, the acute administration of SB-277011-A did not produce extrapyramidal side effects, as indicated by stable lick response-volume ratios and lick response time distributions. These results further support the notion that the D3R is important in mediating the addictive properties of alcohol and suggest that selective blockade of the D3R may constitute a new and useful target for prospective pharmacotherapeutic approaches to alcoholism.     

Selective antagonism at dopamine D3 receptors enhances monoaminergic and cholinergic neurotransmission in the rat anterior cingulate cortex

Recent neuroanatomical and functional investigations focusing on dopamine (DA) D(3) receptors have suggested a potential role of this receptor in psychiatric diseases such as schizophrenia and drug dependence. In line with the key role of the prefrontal cortex in psychiatric disorders, the present study aimed at assessing the effects of the acute systemic administration of the selective DA D(3) receptor antagonist SB-277011-A on the in vivo extracellular levels of monoamines (DA, norepinephrine (NE), and serotonin (5-HT)) and acetylcholine (ACh) in the anterior cingulate subregion of the medial prefrontal cortex. The in vivo neurochemical profile of SB-277011-A (10 mg/kg, i.p.) in the anterior cingulate cortex was compared with both typical and atypical antipsychotics including clozapine (10 mg/kg, s.c.), olanzapine (10 mg/kg, s.c.), sulpiride (10 mg/kg, s.c.), and haloperidol (0.5 mg/kg, s.c.). The acute administration of SB-277011-A, clozapine, and olanzapine produced a significant increase in extracellular levels of DA, NE, and ACh without affecting levels of 5-HT. Sulpiride also significantly increased extracellular DA, but with a delayed onset over SB-277011-A, clozapine, and olanzapine. In contrast, haloperidol failed to alter any of the three monoamines and ACh in the anterior cingulate cortex. These findings add to a growing body of evidence suggesting a differentiation between typical and atypical antipsychotic drugs (APDs) in the anterior cingulate cortex and a role of DA D(3) receptors in desired antipsychotic drug profile. Similar to their effects on DA and NE, SB-277011-A, clozapine, and olanzapine increased extracellular levels of ACh, whereas haloperidol and sulpiride did not alter ACh. The results obtained in the present study provide evidence of the important role of DA D(3) receptors in the effect of pharmacotherapeutic agents that are used for the treatment of psychiatric disorders such as schizophrenia and drug dependence.     

BP-897 Bioprojet

BP-897 is a dopamine D3 receptor agonist which is under development by Bioprojet for the potential treatment of drug craving and vulnerability to relapse that are elicited by drug-associated environmental stimuli; it is undergoing phase I trials [318397,334036,340721]. Preclinical investigations were carried out by Cambridge University and INSERM [295680]. BP-897 functions as a partial agonist in vitro and as either an agonist or an antagonist in vivo. It inhibits cocaine-seeking behavior that depends upon the presentation of drug-associated cues, without having any intrinsic, primary rewarding effects [334036]. In preclinical studies, BP-897 administration before testing reduced cocaine-seeking behavior in rats in a dose-dependent manner [304557,307758,334036]. In D3 receptor knockout mice, BP-897 has no effect [345710]. It does not reduce self-administration of cocaine in monkeys [318397].     

Effects of the selective dopamine D3 receptor antagonist SB-277011A on the reinforcing effects of nicotine as measured by a progressive-ratio schedule in rats

The dopamine D3 receptor is primarily localized within the mesocorticolimbic system, and may therefore have potential as a pharmacotherapeutic target for the treatment of drug dependence. Studies have shown that the selective dopamine D3 receptor antagonist SB-277011A reduces a variety of dependence-related behavioral effects of cocaine, alcohol and heroin. A previous study examining SB-277011A on nicotine self-administration using relatively low doses of the antagonist and a low response requirement for nicotine found no effect on drug-taking behavior per se, whereas reinstatement of nicotine-seeking was reduced. The purpose of the present study was to further examine the effects of higher doses of SB-277011A on nicotine self-administration in rats under a progressive-ratio (PR) schedule, which imposes relatively high response requirements for nicotine. Rats were trained to respond under a PR schedule of either nicotine or food reinforcement. Once responding was stable, SB-277011A (3-56 mg/kg) or vehicle was administered i.p. 1 h prior to the operant session. The highest dose tested significantly decreased the mean number of reinforcers and mean response rates in the nicotine self-administration group, but had no effect on either the mean number of reinforcers or response rate in the food group. In a separate set of experiments, the effects of SB-277011A on locomotor activity were measured. At the dose that significantly decreased nicotine self-administration, total distance traveled was also significantly decreased, suggesting that the effect on operant responding at the high dose of SB-277011A is at a threshold for motor effects and may not be directly mediated by an action at dopamine D3 receptors.     

The selective dopamine D<Subscript>3</Subscript> receptor antagonists SB-277011A and NGB 2904 and the putative partial D<Subscript>3</Subscript> receptor agonist BP-897 attenuate methamphetamine-enhanced brain stimulation reward in rats

Rationale We have previously reported that selective antagonism of brain D₃ receptors by SB-277011A or NGB 2904 significantly attenuates cocaine- or nicotine-enhanced brain stimulation reward (BSR). Objective In the present study, we investigated whether the selective D₃ receptor antagonists SB-277011A and NGB 2904 and the putative partial D₃ agonist BP-897 similarly reduce methamphetamine (METH)-enhanced BSR. Materials and methods Rats were trained to respond for rewarding electrical self-stimulation of the medial forebrain bundle. To assess the degree of drug-induced changes in BSR, a rate–frequency curve shift paradigm was used to measure brain-reward threshold (θ ₀). Results METH (0.1–0.65 mg/kg, i.p.) dose-dependently lowered (∼10–50%) BSR thresholds, producing an enhancement of BSR. Pretreatment with SB-277011A (12 mg/kg, but not 24 mg/kg, i.p.) significantly attenuated METH-enhanced BSR. NGB 2904 (0.1–1.0 mg/kg, but not 10 mg/kg) also attenuated METH-enhanced BSR. SB-277011A or NGB 2904 alone, at the doses tested, had no effect on BSR. Pretreatment with BP-897 (0.1–5 mg/kg) dose-dependently attenuated METH-enhanced BSR. However, when the dose was increased to 10 mg/kg, BP-897 shifted the stimulation–response curve to the right (inhibited BSR itself) in the presence or absence of METH. Conclusions Selective antagonism of D₃ receptors by SB-277011A or NGB 2904 attenuates METH-enhanced BSR in rats, while the METH-enhanced BSR attenuation produced by BP-897 may involve both D₃ and non-D₃ receptors. These findings support a potential use of selective D₃ receptor antagonists for the treatment of METH addiction.     

NADPH oxidase 1 mediates upregulation of thromboxane A2 synthase in human vascular smooth muscle cells: inhibition with iloprost

We have previously reported that selective blockade of brain dopamine D(3) receptors by SB-277011A significantly attenuates cocaine self-administration and cocaine-induced reinstatement of drug-seeking behavior. In the present study, we investigated whether SB-277011A similarly inhibits methamphetamine self-administration and methamphetamine-induced reinstatement to drug-seeking behavior. Male Long-Evans rats were allowed to intravenously self-administer methamphetamine (0.05 mg/kg/infusion) under fixed-ratio 2 (FR2) or progressive-ratio (PR) reinforcement conditions, and some rats were tested for methamphetamine-induced reinstatement of drug-seeking behavior after extinction of self-administration. The effects of SB-277011A on each of these methamphetamine-supported behaviors were then tested. Acute intraperitoneal (i.p.) administration of SB-277011A failed to alter methamphetamine self-administration under FR2 reinforcement, but significantly lowered the break-point for methamphetamine self-administration under PR reinforcement. SB-277011A also significantly inhibited methamphetamine-triggered reinstatement of extinguished drug-seeking behavior. Overall, these data show that blockade of dopamine D(3) receptors by SB-277011A attenuates the rewarding and incentive motivational effects of methamphetamine in rats, supporting the development of selective dopamine D(3) antagonists for the treatment of methamphetamine addiction.     

The selective dopamine D3 receptor antagonists, SB 277011-A and S 33084 block haloperidol-induced catalepsy in rats

SB 277011-A (trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide) and S 33084 [(3aR,9bS)-N[4-(8-cyano-1,3a,4,9b-tetrahydro-3H-benzopyrano[3,4-c]pyrrole-2-yl)-butyl](4-phenyl)benzamide] were already shown to lack cataleptogenic actions. Further to that, we report that SB 277011 exerted a dose-dependent dampening on the development of haloperidol-induced catalepsy in the dose-range of 13.5-30 mg/kg p.o. while S 33084, at the dose of 0.625 mg/kg sc. significantly inhibited catalepsy induced by haloperidol; had no effect at 1.25 mg/kg, and further augmented the effect of haloperidol after 2.5 mg/kg. The compounds also produced effective inhibition when administered 2 hours after haloperidol. The results underline that dopamine D3 receptor antagonist action may have therapeutic value in the treatment of schizophrenia.     

The selective dopamine D3 receptor antagonist SB-277011A reduces nicotine-enhanced brain reward and nicotine-paired environmental cue functions

Increasing evidence suggests that enhanced dopamine (DA) neurotransmission in the nucleus accumbens (NAc) may play a role in mediating the reward and reinforcement produced by addictive drugs and in the attentional processing of drug-associated environmental cues. The meso-accumbens DA system is selectively enriched with DA D3 receptors, a DA receptor subtype increasingly implicated in reward-related brain and behavioural processes. From a variety of evidence, it has been suggested that selective DA D3 receptor antagonism may be a useful pharmacotherapeutic approach for treating addiction. The present experiments tested the efficacy of SB-277011A, a selective DA D3 receptor antagonist, in rat models of nicotine-enhanced electrical brain-stimulation reward (BSR), nicotine-induced conditioned locomotor activity (LMA), and nicotine-induced conditioned place preference (CPP). Nicotine was given subcutaneously within the dose range of 0.25-0.6 mg/kg (nicotine-free base). SB-277011A, given intraperitoneally within the dose range of 1-12 mg/kg, dose-dependently reduced nicotine-enhanced BSR, nicotine-induced conditioned LMA, and nicotine-induced CPP. The results suggest that selective D3 receptor antagonism constitutes a new and promising pharmacotherapeutic approach to the treatment of nicotine dependence.     

Dopamine D<Subscript>3</Subscript> receptor antagonists improve the learning performance in memory-impaired rats

Rationale The dopamine D₃ receptor has been extensively studied in animal models of drug abuse and psychosis; however, less is known on its possible role in cognitive functions.Objectives This study investigated the effects of different D₃ antagonists and a partial agonist on spatial learning performance in a water labyrinth test.Methods Rats had to swim through a labyrinth system by making correct directional turns at three choice-points. The number of errors was recorded in three daily trials for 3 days.Results D₃ antagonists such as the highly selective SB-277011 (24 mg/kg p.o.) and RGH-1756 (1 mg/kg p.o.), the moderately selective U-99194A (12 mg/kg s.c.) and the selective partial D₃ agonist BP-897 (1 mg/kg i.p.) all significantly attenuated the learning deficit caused by FG-7142. Against scopolamine-induced amnesia, SB-277011 (24 mg/kg p.o.) was equally potent in showing protective efficacy; however, two times higher dose levels of U-99194A (24 mg/kg s.c.) and RGH-1756 (2 mg/kg p.o.) were required to attenuate the scopolamine-induced impairment. In contrast to the full antagonists, against scopolamine-induced amnesia, the partial agonist BP-897 (2 mg/kg i.p.) was inactive, even at the two times higher dose level.Conclusions These data suggest that dopamine D₃ receptor antagonists possess cognition-enhancing activity which may be of benefit in the treatment of cognitive dysfunction associated with several psychiatric disorders.     

Blockade of mesolimbic dopamine D<Subscript>3</Subscript> receptors inhibits stress-induced reinstatement of cocaine-seeking in rats

Rationale The dopamine (DA) D₃ receptor is preferentially expressed in the mesolimbic system. We have previously shown that selective D₃ receptor blockade by the novel D₃ antagonist SB-277011A inhibits cocaines reinforcing action and cocaine-induced reinstatement of cocaine-seeking behavior.Objective In the present study, we investigated whether SB-277011A similarly inhibits stress-induced reinstatement of cocaine-seeking behavior.Methods Rats were allowed to self-administer cocaine (0.5 mg/kg per infusion, 3 h per session) for 10–14 days, followed by a once-daily extinction session for 7–14 days during which saline was substituted for cocaine. Extinction criteria were fewer than ten lever-presses per 3-h session for at least 3 consecutive days. After cocaine-seeking behavior was extinguished, each animal was tested twice for footshock-stress-induced reinstatement, once with vehicle (25% hydroxypropyl--cyclodextrin) and once with one of three doses of SB-277011A in counterbalanced fashion.Results During the last 3 days of cocaine self-administration (SA), active lever-presses were approximately 100 per session under fixed-ratio 2 reinforcement (25 mg/kg cocaine per session). After extinction, intermittent footshock (10 min, 0.5 mA, 0.5 s on with a mean inter-shock interval of 40 s) robustly reinstated the cocaine-seeking behavior (8.4±3.6 active lever-presses in last extinction session to 35.3±5.2 in animals after footshock stress). Intraperitoneal (IP) injections of SB-277011A (3, 6, and 12 mg/kg) dose-dependently blocked stress-induced reinstatement of cocaine-seeking. Reinstatement was also blocked by microinjections of SB-277011A (1.5 g/0.5 l per side) bilaterally into the nucleus accumbens, but not into the dorsal striatum.Conclusions The mesolimic DA D₃ receptor plays an important role in mediating stress-induced reinstatement.     

Pharmacological actions of NGB 2904, a selective dopamine D3 receptor antagonist, in animal models of drug addiction

As a continuation of our work with SB-277011A, we have examined the effects of another highly elective dopamine (DA) D3 receptor antagonist, N-(4-[4-{2,3-dichlorophenyl}-1-piperazinyl]butyl)-2-fluorenylcarboxamide (NGB 2904), in animal models of addiction. Our results indicate that by systemic administration, NGB 2904 inhibits intravenous cocaine self-administration maintained under a progressive-ratio (PR) reinforcement schedule, cocaine- or cocaine cue-induced reinstatement of cocaine-seeking behavior, and cocaine- or other addictive drug-enhanced brain stimulation reward (BSR). The action of NGB 2904 on PR cocaine self-administration was long-lasting (1-2 days) after a single injection, supporting its potential use in treatment of cocaine addiction. The effects of NGB 2904 in the BSR paradigm were dose-dependent for both NGB 2904 and cocaine; that is, only lower doses of NGB 2904 were effective, and their putative antiaddiction effect could be overcome by increasing the doses of cocaine or other addictive drugs. A dopamine-dependent mechanism is proposed to explain the effects of NGB 2904 on cocaine's actions in these animal models of drug addiction. The data reviewed in this paper suggest that NGB 2904 or other D3-selective antagonists may have potential in controlling motivation for drug-taking behavior or relapse to drug-seeking behavior, but may have a limited role in antagonizing the acute rewarding effects produced by cocaine or other addictive drugs. In addition, NGB 2904 may also act as a useful tool to study the role of D3 receptors in drug addiction.     

The anti-influenza drug oseltamivir evokes hypothermia in mice through dopamine D2 receptor activation via central actions

Oseltamivir has a hypothermic effect in mice when injected intraperitoneally (i.p.) and intracerebroventricularly (i.c.v.). Here we show that the hypothermia evoked by i.c.v.-oseltamivir is inhibited by non-selective dopamine receptor antagonists (sulpiride and haloperidol) and the D₂-selective antagonist L-741,626, but not by D₁/D₅-selective and D₃-selective antagonists (SCH-23390 and SB-277011-A, respectively). The hypothermic effect of i.p.-administered oseltamivir was not inhibited by sulpiride, haloperidol, L-741,626 and SCH-23390. In addition, neither sulpiride, haloperidol nor SCH-23390 blocked hypothermia evoked by i.c.v.-administered oseltamivir carboxylate (a hydrolyzed metabolite of oseltamivir). These results suggest that oseltamivir in the brain induces hypothermia through activation of dopamine D₂ receptors.     

Cocaine-seeking behavior in response to drug-associated stimuli in rats: involvement of D3 and D2 dopamine receptors.

Previous studies employed a second-order schedule paradigm maintained by cocaine reinforcement to show that BP897, a dopamine D(3) partial agonist, selectively modulated drug-seeking behavior. We investigated its effect on drug-seeking behavior induced by presentation of stimuli associated with and predictive of cocaine availability after a period of extinction and in the absence of any further cocaine. Male rats were trained to associate discriminative stimuli (S(D)) with the availability of intravenous (i.v.) 0.25 mg/0.1 ml/infusion cocaine (S(D+)) or no-reward (S(D-)) saline solution. Each infusion of cocaine or saline was followed by a response-cue signaling 20-s time-out (TO). After meeting the self-administration training criterion rats were placed on extinction conditions during which i.v. solutions and S(D)s were withheld. Every other 3 days on which rats met the extinction criterion, reinstatement tests were conducted, presenting the S(D+) or S(D-) noncontingently together with a contingent presentation of cocaine- or saline-cues signaling 20-s TO. Regardless of the order of presentation or the nature of the stimuli (auditory or visual), cocaine-associated but not saline-associated stimuli reinstated responding on the previously active lever. Presentation of cocaine-associated stimuli induced lasting drug-seeking behavior for at least eight test sessions. BP897 (1.0 mg/kg i.p.) significantly attenuated this behavior. Since it has been reported that BP897 can interact with a panel of different receptors with high affinity, we evaluated the effects of 7-OH-DPAT, an agonist to D(3) receptors, raclopride, a preferential antagonist to D(2) receptors, and WAY 100,635, an antagonist at 5-HT(1A) receptors, on drug-seeking behavior. 7-OH-DPAT (0.1-3.0 mg/kg i.p.) had biphasic effects on reinstatement induced by the cocaine-associated cues, low dosages reducing and high dosages increasing the impact of cocaine-associated stimuli on rats' behavior. Raclopride (0.1, 0.3 mg/kg s.c.) completely prevented drug-seeking behavior induced by the reintroduction of cocaine-associated stimuli. WAY 100,635 (0.1-1.0 mg/kg s.c.) had no effect on this behavior. These results, while confirming that the partial agonist at the D(3) receptors, BP897, might be a useful medication, also suggest a role of D(2) receptors in cue-induced cocaine-seeking behavior.     

The effects of dopamine D3 agonists and antagonists in a nonhuman primate model of tardive dyskinesia

Tardive dyskinesia (TD), a serious complication of antipsychotic dopamine (DA) antagonist treatment, has been hypothesised to develop due to a dominant DA D1 relative to DA D2 receptor function. Recent genetic and pharmacological studies implicate the DA D3 receptor in TD. The present study examined the role of the DA D3 receptor in relation to the DA D1/D2 imbalance hypothesis of TD in nonhuman primates. Eight Cebus monkeys displaying mild to severe TD due to previous chronic exposure to DA D2 antagonists were acutely injected with SKF 81297 (DA D1 agonist) 0.3 and 0.6 mg/kg, pramipexole (DA D3>D2 agonist) 0.025-0.1 mg/kg, CIS-8-OH-PBZI (DA D3 agonist) 5-10 mg/kg and SB-27701-A (DA D3 antagonist) 1-5 mg/kg and rated for oral dyskinesia. SKF 81297, 0.3 and 0.6 mg/kg, exacerbated TD. Pramipexole and CIS-8-OH-PBZI reduced SKF 81297-induced TD, while SB-27701-A had no effect. When administered alone, SB-27701-A increased TD relative to placebo, while pramipexole and CIS-8-OH-PBZI had no significant effect. Pramipexole did, however, ameliorate TD in those monkeys with severe TD. These results point towards a role of the DA D3 receptor in TD, but indicate that the DA D2 receptor may also play an essential role.